In recent studies aimed at defining the selective lysis of tumor cells by murine natural killer (NK) cells, we have isolated, from a methyl cholanthrene-induced DBA/2 lymphoma L5178, two clones of cells, one particularly susceptible to lysis by NK cells, the other almost totally resistant. Serological analysis showed no marked differences in cell surface alloantigen display on the two cell lines. Similarly, they were indistinguishable in their susceptibility to alloimmune cytotoxic T cells. The cells thus appear to be NK susceptibility variants. Preliminary biochemical characterization of the L5178 variants revealed that the susceptible cell line showed marked increases in the cell surface display of asialo GM2 glycolipid; the unsusceptible variant showed undetectable amounts of this compound. These differences were established both biochemically (using CHCl3:MeOH extraction followed by thin-layer chromatography and resorcinol:orcinol staining) and immunochemically using antisera specific for asialo GM2. In the work proposed, we wish to characterize more completely cell surface macromolecule display (protein, glycoprotein, glycolipid) on the cell variants of L5178 which differ in their susceptibility to NK cells. In an attempt to address the hypothesis that NK cell populations might be directed against cell surface glycolipids we intend: a) to increase glycolipid display on insusceptible cells by fusion with liposomes of defined content, b) to systematically "block" glycolipids on susceptible target cells with defined antisera and to note effects on NK cell mediated lysis, and c) to assess the susceptibility of glycolipid containing liposomes to NK attack. In a more general approach to the issue of the specificity of NK cell mediated attack we intend to use controlled protease and glycosidase digestion of the target cell surface and to assess the effects of such treatment on NK cell mediated lysis.